Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism

Abstract

The inflammasomes are intracellular complexes that have an important role in cytosolic innate immune sensing and pathogen defense. Inflammasome sensors detect a diversity of intracellular microbial ligands and endogenous danger signals and activate caspase-1, thus initiating maturation and release of the proinflammatory cytokines interleukin-1β and interleukin-18. These events, although crucial to the innate immune response, have also been linked to the pathology of several inflammatory and autoimmune disorders. The natural isothiocyanate sulforaphane, present in broccoli sprouts and available as a dietary supplement, has gained attention for its antioxidant, anti-inflammatory, and chemopreventive properties. We discovered that sulforaphane inhibits caspase-1 autoproteolytic activation and interleukin-1β maturation and secretion downstream of the nucleotide-binding oligomerization domain-like receptor leucine-rich repeat proteins NLRP1 and NLRP3, NLR family apoptosis inhibitory protein 5/NLR family caspase-1 recruitment domain-containing protein 4 (NAIP5/NLRC4), and absent in melanoma 2 (AIM2) inflammasome receptors. Sulforaphane does not inhibit the inflammasome by direct modification of active caspase-1 and its mechanism is not dependent on protein degradation by the proteasome or de novo protein synthesis. Furthermore, sulforaphane-mediated inhibition of the inflammasomes is independent of the transcription factor nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and the antioxidant response-element pathway, to which many of the antioxidant and anti-inflammatory effects of sulforaphane have been attributed. Sulforaphane was also found to inhibit cell recruitment to the peritoneum and interleukin-1β secretion in an in vivo peritonitis model of acute gout and to reverse NLRP1-mediated murine resistance to Bacillus anthracis spore infection. These findings demonstrate that sulforaphane inhibits the inflammasomes through a novel mechanism and contributes to our understanding of the beneficial effects of sulforaphane.

Sulforaphane induces neurovascular protection against a systemic inflammatory challenge via both Nrf2-dependent and independent pathways

“…These findings are supported by other groups describing Nrf2 independent effects of SFN in e.g. in cycle arrest and apoptosis, and inhibition of angiogenesis, histone deacetylases and cytochrome P450 [31]. Recently Greaney et al ., 2015 focused studies on inflammasomes, as these have an important role in cytosolic innate immune sensing and pathogen response.…”

“…Recently Greaney et al ., 2015 focused studies on inflammasomes, as these have an important role in cytosolic innate immune sensing and pathogen response. They found that SFN-mediated inhibition of inflammasomes is also independent of Nrf2 [31]. Other evidence points to SFN reacting directly with other cellular targets such as toll like receptor 4 (via the suppression of both ligand-induced and ligand-independent oligomerization of TLR4) [32] and tubulin [33].…”

Sulforaphane Protects Pancreatic Acinar Cell Injury by Modulating Nrf2‐Mediated Oxidative Stress and NLRP3 Inflammatory Pathway

“…Our data revealed that NLRP3 inflammasome activation is associated with cerulein-induced inflammation in acini and suppressed by SFN. Earlier reports have suggested that SFN inhibited caspase-1 cleavage and IL-1 β maturation for the NLRP1b, NLRP3, NAIP5/NLRC4, and AIM2 inflammasomes in immune cells [18]. This study, for the first time, has demonstrated that SFN blocked the NLRP3 inflammasome activation in cerulein-induced pancreatic acini.…”

“…SFN is known to be important in the maintenance of cellular redox balance [14] and has earlier been used as an effective phytochemical antioxidant in studies of gastrointestinal and pulmonary diseases [15–17]. In addition, SFN has been reported to inhibit multiple inflammasomes in immune cells [18]. Recent findings indicate that the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome, provides the link between acinar cell death and inflammation during the development of AP; and activation of NLRP3 inflammasome is involved in the development of AP [19], which is inhibited by antioxidants like hydrogen-rich saline [12].…”

Glucoraphanin Ameliorates Obesity and Insulin Resistance Through Adipose Tissue Browning and Reduction of Metabolic Endotoxemia in Mice

“…-/-mice Although the Keap1-Nrf2 pathway is a well-known target of sulforaphane, this isothiocyanate has also been reported to modulate different biological pathways independent of the Keap1-Nrf2 pathway (24,25). To determine whether the anti-obesity and insulin-sensitizing effects of glucoraphanin are mediated through Nrf2, the effects of glucoraphanin on energy balance and glucose metabolism were assessed in NC-and HFD- Fig.…”